Avonex

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action by which AVONEX exerts its
effects in patients with multiple sclerosis is unknown.

Pharmacodynamics

Interferons (IFNs) are a family of naturally occurring
proteins, produced by eukaryotic cells in response to viral infection and other
biologic agents. Three major types of interferons have been defined: type I
(IFN-alpha, beta, epsilon, kappa and omega), type II (IFN–gamma) and type III (IFN-lambda). Interferon-beta is a member of the type I subset of interferons. The type I interferons
have considerably overlapping but also distinct biologic activities. The
bioactivities of all IFNs, including IFN-beta, are induced via their binding to
specific receptors on the membranes of human cells. Differences in the
bioactivites induced by the three major subtypes of IFNs likely reflect
differences in the signal transduction pathways induced by signaling through
their cognate receptors.

Interferon beta exerts its biological effects by binding
to specific receptors on the surface of human cells. This binding initiates a
complex cascade of intracellular events that leads to the expression of
numerous interferon-induced gene products and markers. These include 2', 5'- oligoadenylate
synthetase, β2-microglobulin, and neopterin. These products have been measured
in the serum and cellular fractions of blood collected from patients treated
with AVONEX.

Clinical studies conducted in multiple sclerosis patients
showed that interleukin 10 (IL-10) levels in cerebrospinal fluid were increased
in patients treated with AVONEX compared to placebo. Serum IL-10 levels
maximally were increased by 48 hours after intramuscular injection of AVONEX
and remained elevated for 1 week. However, no relationship has been established
between absolute levels of IL-10 and clinical outcome in multiple sclerosis.

Pharmacokinetics

Pharmacokinetics of AVONEX in multiple sclerosis patients
have not been evaluated. The pharmacokinetic and pharmacodynamic profiles of
AVONEX in healthy subjects following doses of 30 micrograms through 75
micrograms have been investigated. Serum levels of AVONEX as measured by
antiviral activity are slightly above detectable limits following a 30
microgram intramuscular dose, and increase with higher doses.

After an intramuscular dose, serum levels of AVONEX
generally peak at 15 hours post-dose (range: 6-36 hours) and then decline at a
rate consistent with a 19 (range: 8-54) hour elimination half-life.

Subcutaneous administration of AVONEX should not be
substituted for intramuscular administration as there is no data establishing
that subcutaneous and intramuscular administration of AVONEX result in equivalent
pharmacokinetic and pharmacodynamic parameters.

Biological response markers (e.g., neopterin and β2-microglobulin)
are induced by AVONEX following parenteral doses of 15 micrograms through 75
micrograms in healthy subjects and treated patients. Biological response marker
levels increase within 12 hours of dosing and remain elevated for at least 4
days. Peak biological response marker levels are typically observed 48 hours
after dosing. The relationship of serum AVONEX levels or levels of these induced
biological response markers to the mechanisms by which AVONEX exerts its
effects in multiple sclerosis is unknown.

Clinical Studies

The clinical effects of AVONEX in patients with relapsing
forms of multiple sclerosis (MS) were studied in two randomized, multicenter,
double-blind, placebo-controlled studies in patients with MS (Studies 1 and 2).
Safety and efficacy of treatment with AVONEX beyond 3 years is not known.

In Study 1, 301 patients received either 30 micrograms of
AVONEX (n=158) or placebo (n=143) by intramuscular injection once weekly.
Patients received injections for up to 2 years, and continued to be followed
until study completion. Two hundred eighty-two patients completed 1 year on
study, and 172 patients completed 2 years on study. There were 144 patients
treated with AVONEX for more than 1 year, 115 patients for more than 18 months
and 82 patients for 2 years.

All patients had a definite diagnosis of multiple
sclerosis of at least 1 year duration and had at least 2 exacerbations in the 3
years prior to study entry (or 1 per year if the duration of disease was less
than 3 years). At entry, study participants were without exacerbation during
the prior 2 months and had Kurtzke Expanded Disability Status Scale (EDSS3)
scores ranging from 1.0 to 3.5. The EDSS is a scale that quantifies disability
in patients with MS and ranges from 0 (normal neurologic exam) to 10 (death due
to MS). Patients with chronic progressive multiple sclerosis were excluded from
this study.

Disability

The primary outcome assessment was time to progression in
disability, measured as an increase in the EDSS score of at least 1 point that
was sustained for at least 6 months. An increase in EDSS score reflects
accumulation of disability. This endpoint was used to help distinguish
permanent increase in disability from a transient increase due to an
exacerbation.

As shown in Figure 1, the time to onset of sustained
progression in disability was significantly longer in AVONEX-treated patients
than in placebo-treated patients in Study 1 (p = 0.02). The percentage of
patients progressing by the end of 2 years was 35% for placebo-treated patients
and 22% for AVONEX-treated patients. This represents a 37% relative reduction
in the risk of accumulating disability in the AVONEX-treated group compared to
the placebo-treated group.

Figure 1: Time to Onset of Sustained Disability
Progression in Patients with MS in Study 11

1 Kaplan-Meier Methodology; Disability progression was
defined as at least a 1 point increase in EDSS score sustained for at least 6
months

The distribution of confirmed EDSS change from study
entry (baseline) to the end of the study is shown in Figure 2. There was a
statistically significant difference between the AVONEX and placebo groups in
confirmed change for patients with at least 2 scheduled visits (p = 0.006).

Figure 2: Confirmed Change in EDSS from Study Entry to
End of Study 1

Exacerbations

The rate and frequency of MS exacerbations were secondary
outcomes. For all patients included in the study, irrespective of time on
study, the annual exacerbation rate was 0.67 per year in the AVONEX-treated
group and 0.82 per year in the placebo-treated group (p = 0.04).

AVONEX treatment significantly decreased the frequency of
exacerbations in the subset of patients who were enrolled in the study for at
least 2 years (87 placebo-treated patients and 85 AVONEX-treated patients; p =
0.03; see Table 3).

MRI Results

Gadolinium (Gd)-enhanced and T2-weighted magnetic
resonance imaging (MRI) scans of the brain were obtained in most patients at
baseline and at the end of 1 and 2 years of treatment. Secondary outcomes
included Gd-enhanced lesion number and volume, and T2-weighted lesion volume.
Gd-enhancing lesions seen on brain MRI scans represent areas of breakdown of
the blood brain barrier thought to be secondary to inflammation. AVONEX-treated
patients demonstrated significantly lower Gd-enhanced lesion number after 1 and
2 years of treatment than placebo-treated patients (p ≤ 0.05; see Table
3). The volume of Gd-enhanced lesions showed similar treatment effects in the
AVONEX and placebo groups (p ≤ 0.03). Percentage change in T2-weighted
lesion volume from study entry to Year 1 was significantly lower in AVONEX-treated
than placebo-treated patients (p = 0.02). A significant difference in T2- weighted
lesion volume change was not seen between study entry and Year 2 in the AVONEX and
placebo groups.

The exact relationship between MRI findings and the
clinical status of MS patients is unknown. The prognostic significance of MRI
findings in these studies has not been evaluated.

Summary of Effects of Clinical and MRI Endpoints in Study
1

A summary of the effects of AVONEX on the clinical and
MRI endpoints of this study is presented in Table 3.

Table 3: Clinical and MRI Endpoints in Patients with
MS in Study 1

Endpoint

Placebo

AVONEX

P-Value

PRIMARY ENDPOINT:

Time to sustained progression in disability (N: 143, 158)1

--- See Figure 1 ---

0.022

Percentage of patients progressing in disability at 2 years (Kaplan-Meier estimate)1

35%

22%

SECONDARY ENDPOINTS: DISABILITY

Mean confirmed change in EDSS from study entry to end of study (N: 136, 150)1

Note: (N: , ) denotes the number of evaluable placebo and
AVONEX patients, respectively.1Patient data included in this analysis represent variable periods
of time on study.2Analyzed by Mantel-Cox (logrank) test.3Analyzed by Mann-Whitney rank-sum test.4Analyzed by Cochran-Mantel-Haenszel test.5Analyzed by likelihood ratio test.

In Study 2, 383 patients who had recently experienced an
isolated demyelinating event involving the optic nerve, spinal cord, or
brainstem/cerebellum, and who had lesions typical of multiple sclerosis on
brain MRI, received either 30 micrograms of AVONEX (n = 193) or placebo (n = 190)
by intramuscular injection once weekly. Patients were enrolled into the study
over a twoyear period and followed for up to three years or until they
developed a second clinical exacerbation in an anatomically distinct region of
the central nervous system.

Exacerbations

In Study 2, the primary outcome measure was time to
development of a second exacerbation in an anatomically distinct region of the
central nervous system. Time to development of a second exacerbation was
significantly delayed in AVONEX-treated compared to placebo-treated patients (p
= 0.002). The Kaplan-Meier estimates of the percentage of patients developing
an exacerbation within 24 months were 39% in the placebo group and 21% in the
AVONEX group (see Figure 3). The relative rate of developing a second
exacerbation in the AVONEX group was 0.56 of the rate in the placebo group (95%
confidence interval 0.38 to 0.81).

Figure 3: Time to onset of a Second Exacerbation in
Study 21

1 Kaplan-Meier Methodology

MRI Findings

Secondary outcomes were brain MRI measures, including the
cumulative increase in the number of new or enlarging T2 lesions, T2 lesion
volume at baseline compared to results at 18 months, and the number of
Gd-enhancing lesions at 6 months. See Table 4 for the MRI results.